Planning the Treatment Journey: How Doctors Sequence Therapies in CLL

“Because some patients who are actively working prefer to take a pill even if it takes longer,” she adds.

The goal of sequencing is to keep the leukemia controlled for as long as possible, manage side effects, maintain quality of life, and preserve effective treatments that can be used later if the disease returns or stops responding.

For others, especially those considering combination approaches, the strategy is different.

“When you do a combination of two drugs… and you have a fixed‑ratio treatment strategy, the aim is to get into a remission that is so deep that the disease will take time to come back, or maybe not come back for many years,” Dr. Barrientos notes. “But again, it comes with its own toxicities. Patients need to understand the implications of taking a pill every day versus taking something for a fixed ratio, especially in someone older.”

When planning a treatment path, doctors weigh all of these considerations — the biological features of your CLL, genetic markers, your overall health, what treatments you’ve had before, how well those treatments worked, and your personal goals and preferences.

Options When Treatment Stops Working

A type of targeted therapy known as BTK inhibitors has been one of the most important advances in CLL treatment. These medications block a protein called Bruton’s tyrosine kinase (BTK), which helps CLL cells survive and grow. Commonly used BTK inhibitors include ibrutinib, acalabrutinib, and zanubrutinib.

For many patients, BTK inhibitors provide long-lasting control of CLL and are taken as daily oral medications. However, over time, some patients may need to stop treatment.

Doctors first consider why the BTK inhibitor was stopped. If the leukemia grows while taking the medication, this may indicate that the CLL has developed resistance. If the medication is stopped because of side effects, such as heart rhythm problems, bleeding issues, or other concerns, a different treatment approach may be considered.

For patients whose CLL progresses after treatment with these BTK inhibitors, pirtobrutinib is a newer type of BTK inhibitor that works differently from earlier types. Because it binds to BTK in a different way, it may remain effective in some patients whose leukemia has developed resistance to previous BTK inhibitors.

WATCH: CLL Treatment Decision Making

“Right now, pirtobrutinib (Jaypirca) has been approved for patients with relapse disease after the use of one of the BTK inhibitors that are covalently bound to the BTK. However, the only lingering hangup is with sequencing. We don’t know exactly what’s going to happen when you stop responding to pirtobrutinib (Jayperka),” Dr. Barrientos says.

Another important class of targeted therapy is the BCL-2 inhibitor venetoclax. Venetoclax works differently from BTK inhibitors by blocking a protein that helps CLL cells survive. Because it attacks leukemia through a different pathway, it is an important option both as an initial treatment and after other therapies.

Understanding Your Treatment Timeline

One advantage of venetoclax-based treatment is that it is often given for a fixed duration, allowing patients to complete therapy and have a period of time without treatment.

However, starting venetoclax requires careful monitoring because it can cause rapid breakdown of leukemia cells, known as tumor lysis syndrome. Patients may need frequent blood tests, careful hydration, and additional monitoring at the beginning of treatment.

WATCH: Understanding BTK Inhibitors

For some patients who previously had a long-lasting response to venetoclax-based therapy, doctors may consider using venetoclax again when the disease returns, depending on factors such as how long the previous response lasted, what other treatments have been given, and the patient’s overall health.

There is no single treatment sequence that is right for every patient. Instead, doctors consider how each therapy fits into the overall treatment plan.

For example, a patient who starts with a BTK inhibitor may later receive venetoclax-based therapy if the leukemia progresses. A patient who begins with venetoclax-based treatment may later receive a BTK inhibitor or another targeted therapy when additional treatment is needed.

The choice depends on:

• Previous therapies
• The length of time the disease was controlled for
• The reason the treatment was changed
• Genetic features of leukemia
• Side effects from prior treatments
• Your treatment goals

CLL treatment is viewed as a long-term strategy rather than a series of separate decisions.

The number of available CLL treatments continues to grow. As more options become available, doctors are working toward a more personalized approach, matching the right treatment to the right patient at the right time.

Important questions about sequencing, including whether newer therapies should be used earlier in treatment, how best to combine targeted therapies, how to overcome resistance, and how to achieve longer periods of disease control while maintaining quality of life, are being investigated.

Dr. Barrientos says there are ongoing clinical trials studying the use of pirtobrutinib earlier and compared against the standard routine.

“So far, even though the data is not long enough and not mature enough, it’s looking really good and very well tolerated, with excellent response rates and excellent time in remission,” she notes.

Questions To Ask Your Doctor

• What do you recommend as the best first-line or initial treatment for me?
• What options will we consider if my cancer progresses after treatment?
• What if I prefer not to be on medication indefinitely?
• What side effects of targeted therapy should I be aware of?

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